Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Insights into lysosomal cobalamin trafficking : lessons learned from cblF disease

Vitamin B(12) (cobalamin) is essential in animals and humans for metabolism of methylmalonic acid, for the remethylation of homocysteine to methionine and, consequently, for all S-adenosylmethionine-dependent methylation reactions, including DNA synthesis. In man, cobalamin deficiency leads to anemia and neurologic and cognitive impairment. In the cblF inborn error of vitamin B(12) metabolism, free vitamin accumulates in lysosomes and cannot be converted to cofactors for mitochondrial methylmalonyl-CoA mutase and cytosolic methionine synthase. Recent work has shown that this defect is caused by mutations in the lysosomal membrane protein LMBD1, which shows significant homology to lipocalin membrane receptors, thereby indicating that LMBD1 is a lysosomal membrane exporter for cobalamin

Autoimmune Dacryoadenitis of NOD/LtJ Mice and Its Subsequent Effects on Tear Protein Composition

Sjögren’s syndrome (SjS) is a human autoimmune disease characterized by exocrine dysfunction resulting from chronic autoimmune attack primarily against the lacrimal and/or salivary glands. Although, we previously established a good correlation between SjS in humans and autoimmune exocrinopathy in NOD/LtJ mice an in-depth evaluation of lacrimal gland disease in the NOD/LtJ mouse has remained limited. This leaves a major gap in our understanding of the dacryoadenitis/keratoconjunctivitis sicca in this model. Here we characterize the development of the autoimmune dacryoadenitis in NOD/LtJ and NOD.B10-H2b mice in comparison with age- and sex-matched nonautoimmune CD1 mice. We observed a decline in tear production beginning at 8 weeks of age in both NOD/LtJ and NOD.B10-H2b mice, continuing throughout the 40 to 46 weeks studied. This correlated with a quantifiable increase in mixed T- and B-lymphocyte infiltrations in the extraorbital lacrimal glands. In addition, temporal differences in tear protein expression between NOD/LtJ and CD1 mice were identified using two-dimensional gel electrophoresis and tandem mass spectrometry. Thus, using this model we can identify potentially important pathophysiological mechanisms of the autoimmune attack and possible diagnostic markers for development of SjS-associated dacryoadenitis